ANXIOSTAR-60

Quick Overview

Our aim is to reach out to the globe within shortest possible time frame.

To promote this objective, not only we distribute and market our CNS range of products globally through our distribution channels but we also undertake ‘contract manufacturing’& ‘formulation development ’of our wide range of generic products such as ANXIOSTAR 60 which contains Duloxetine Hydrochloride Eq. to Duloxetine 60 mg.

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics is dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.

Absorption and Distribution - Orally administered duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (C of max) duloxetine occurring 6 hours post dose. Food does not affect the C of max duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose ascompared to a morning dose.

The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and a1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.

Metabolism and Elimination - Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro.

Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.

MECHANISM OF ACTION:

Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro.

Duloxetine does not inhibit monoamine oxidase (MAO). Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine, consideration should be given to the possibility that they might be drug-related.

• Efficacy was established in four short-term and one maintenance trial in adults.

• Generalized Anxiety Disorder (GAD).

• Efficacy was established in three short-term and one maintenance trial in adults.

• Diabetic Peripheral Neuropathic Pain (DPNP).

• Fibromyalgia (FM).

• Chronic Musculoskeletal Pain.

CONTRAINDICATIONS

• Use of a monoamine oxidase inhibitor concomitantly or in close temporal proximity.

• Use in patients with uncontrolled narrow-angle glaucoma.

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Duloxetine or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Duloxetine is not approved for use in pediatric patients, Use in Specific Populations, and Information for Patients.

PRECAUTIONS:

• Suicidality: Monitor for clinical worsening and suicide risk.

• Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with Duloxetine. Duloxetine should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Duloxetine should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

• Orthostatic Hypotension and Syncope: Cases have been reported with duloxetine therapy.

• Abnormal Bleeding: Duloxetine may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation.

• Major Depressive Disorder - It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with duloxetine as monotherapy. Duloxetine should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment

• Generalized Anxiety Disorder - It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with duloxetine as monotherapy. Duloxetine should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment.

• Diabetic Peripheral Neuropathic Pain - As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Duloxetine must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.

• Fibromyalgia - Fibromyalgia is recognized as a chronic condition. The efficacy of Duloxetine in the management of fibromyalgia has been demonstrated in placebo-controlled studies up to 3 months. The efficacy of duloxetine was not demonstrated in longer studies; however, continued treatment should be based on individual patient response.

• Chronic Musculoskeletal Pain - The efficacy of duloxetine has not been established in placebo-controlled studies beyond 13 weeks.

Fetal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension and vomiting.

Management of Overdose

There is no specific antidote to Duloxetine, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a largebore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.

Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and C by an average of one-third, max although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken duloxetine and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation. The physician should consider contacting a poison control center for additional information.